The compound, which is the subject of the present invention (Compound I, trans-1-((1R,3S)-6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine) has the general formula (1).

A group of compounds structurally related to Compound I, i.e. trans isomers of 3-aryl-1-(1-piperazinyl)indanes substituted in the 2- and/or 3-position of the piperazine ring, has been described in EP 638 073; Bøgesø et al. in J. Med. Chem., 1995, 38, 4380-4392 and Klaus P. Bøgesø in “Drug Hunting, the Medicinal Chemistry of 1-Piperazino-3-phenylindans and Related Compounds”, 1998, ISBN 87-88085-10-4I. These compounds are described as having high affinity for dopamine (DA) D1 and D2 receptors and the 5-HT2 receptor and are suggested to be useful for treatment of several diseases in the central nervous system, including schizophrenia.
An enantiomer corresponding to the compound of the formula (I) but differing in that it has a methyl group instead of a hydrogen on the piperazine has been disclosed in Bøgesø et al. in J. Med. Chem., 1995, 38, 4380-4392, see table 5, compound (−)-38. This publication concludes that the (−)-enantiomers of compound 38 is a potent D1/D2 antagonists showing some D1 selectivity in vitro while in vivo it is equipotent as D1 and D2 antagonist. The compound is described as a potent 5-H T2 antagonist, having high affinity for α1 adrenoceptors.
None of the above references disclose the specific enantiomeric form above (Compound I) or the medical use thereof. The trans isomer in the form of the racemate of Compound 1 is only indirectly disclosed as an intermediate in the synthesis of compound 38 in Bøgesø et al. in J. Med. Chem., 1995, 38, 4380-4392) while the medical use of Compound I or of its corresponding racemate is not described.
The aetiology of schizophrenia is not known, but the dopamine hypothesis of schizophrenia (Carlsson, Am. J. Psychiatry 1978, 135, 164-173), formulated in the early 1960s, has provided a theoretical framework for understanding the biological mechanisms underlying this disorder. In its simplest form, the dopamine hypothesis states that schizophrenia is associated with a hyperdopaminergic state, a notion which is supported by the fact that all antipsychotic drugs on the market today exert some dopamine D2 receptor antagonism (Seeman Science and Medicine 1995, 2, 28-37). However, whereas it is generally accepted that antagonism of dopamine D2 receptors in the limbic regions of the brain plays a key role in the treatment of positive symptoms of schizophrenia, the blockade of D2 receptors in striatal regions of the brain causes extrapyramidal symptoms (EPS). As described in EP 638 073 a profile of mixed dopamine D1/D2 receptor inhibition has been observed with some so-called “atypical” antipsychotic compounds, in particular with clozapine, used in treatment of schizophrenic patients. Central al antagonistic actions has also been suggested to contribute in improving antipsychotic properties (Millan et al, JPET, 2000, 292, 38-53).
Further, selective D1 antagonists have been connected to treatment of sleep disorders and alcohol abuse (D. N. Eder, Current Opinion in Investigational Drugs, 2002 3(2):284-288). Dopamine may also play an important role in the etiology of affective disorders (P. Willner, Brain. Res. Rev. 1983, 6, 211-224, 225-236 and 237-246; J. Med. Chem. 1985, 28, 1817-1828).
In EP 638 073 is described how compounds having affinity for 5-HT2 receptors, in particular 5-HT2 receptors antagonists, have been suggested for treatment of different diseases, such as schizophrenia including the negative symptoms in schizophrenic patients, depression, anxiety, sleep disturbance, migraine attacks and neuroleptic-induced parkinsonism. 5-HT2 receptor antagonism has also been suggested to reduce the incidence of extrapyramidal side effects induced by classical neuroleptics (Balsara et al. Psychopharmacology 1979, 62, 67-69).